Jsqseserpic acid lactone



tries 3,051,713 M-JSORESERPIC ACID LACTONE v Georges Muller, Nogent-sur-Marne, France, assignor, by mesne assignments, to Roussel-UCLAF, S.A., Paris, France, a corporation of France No Drawing. Filed Feb. 11, 1958, Ser. No. 714,473 4 Claims. ((31. 260287) I 5 ona The invention also provides a method for the synthesis of a new lactone intermediate in both its racemic and optically active forms, from which the methyl dehydroreserpate is made by conversion with an alkaline methoxide, namely the lactone of 1818-hydroxy-11,17a-dimethoxy-16B-carboxy-3(l4)-dehydro 20a yohimbane. Both the lactone and the methyl dehydroesenpate prepared therefrom are valuable novel materials in the synthetic production of reserpine, since the methyl A dehydroreserpate may be reduced by known methods to methyl reserpate, from which reserpine itself may be obtained directly. Reserpine is an alkaloid having known valuable pharmacodynamic and tranquilizer properties. The methyl dehydroreserpate may also be transformed into valuable drugs by esterification of the free hydrOXY group by means of an acid, said acid being applied in the form of an active functional derivative, such as an anhydride, a mixed anhydride, or an acid chloride, in presence of a suitable condensing agent under conventional reaction conditions. Examples of acids which may be employed to esterify methyl A -dehydroreserpate in this manner include substituted benzoic or cinnamic acids, such as 3.4.5-t1imethoxybenzoic acid or 3.4.5-trimethoxycinnamic acid,

In order better to understand the relationships existing among the starting materials, intermediates, and final products, reference may be had to the following equations nary base derivedfrom (1).

on o onto IV 6cm on o CHaOzC- OH V V I) 60H:

In these equations, the starting material (I) is the lactone of 18B-hydroxy-11,17u-dimethoxy-3-oxo-16p-carboxy-2,3- seco-20u-yohimbane, and compound (II) is the quater- Compound (I) and this quaternary base (11) are prepared by saponification of 18p acetoxy 11,170: dimethoxy 3 oxo 165 methoxy-carbonyl-2.3-seco-20a-yohimbane, followed by a lactonization of the hydroxylated acid thus obtained and cyclization of the latter to form the quaternary base. The quaternary base (H) cannot be purified, and salt formation is required to isolate it. This complicates its use in subsequent conversions, so that, for example, its transformation into the lactone of reserpic acid (IV) involves a reduction, the yield of which is quite low.

It has now been found that the lactone of 18,6-hydroxy- 11,170: dimethoxy 3 oxo 16,3 carboxy 2,3 seco- 20u-yohimbane (I) may be converted directly into the lactone of 18fi-hydroxy-1l,17udimethoxy-16,5-carboxy- 3(14)-dehydro-20a-yohimbane (III), if the cyclization, for example with phosphorus oxychloride, is followed by an ammonia treatment which has the effect of causing a migration of the double bond of the quaternary base (II) from 3,4 into 3,14, without the necessity of isolating the latter. Lactone III is a new compound, which, in addition to producing the methyl A -dehydroreserpate of the invention, crystallizes and is easily purified. It represents a valuable intermediate product in the synthesis of reserpine. It is possible to convert it, by reduction with zinc in acetic acid, for example, into reserpic acid lactone (IV), from which methyl reserpate (VI) and reserpine may be produced.

The process of the invention consists substantially in treating the racemic or optically active lactone of 18ohydroxy-llJh-dimethoxy 3 oxo-l6 3-carboxy-2,3-seco ZOa-yOhimIbane (I) with phosphorus oxychloride. The excess reagent is eliminated, it is taken up cold with a suitable solvent, such as a lower aliphatic alcohol as, for example, methanol, concentrated ammonia is added, then, water, and the resulting lactone of l8fl-hydroxy-ll,l7udimethoxy-l6fi-carboxy-3( 14) dehydro 20a-yohimbane (III) is extracted. The extraction is carried out with a solvent such as methylene chloride, which is not miscible with water. Said lactoneis crystallized, is treated with an alkaline methoxide, such as, for example, sodium methylate, under methanol reflux, is evaporated to dryness in vacuo, is treated with ammonia, extraction is performed according to the usual methods, and the racemic or optically active methyl A -dehydroreserpate (V) is isolated. V

The examples which follow serve to illustrate preferred embodiments of the invention without however limiting its scope as defined in the appended claims. It will be understood that it is possible to change the nature of the solvents and of the reagents, the temperatures, reaction times and the order of introducing the reagents without thereby exceeding the scope of the invention. The melting points given are corrected; they represent instantaneous melting and have been determined on the Maquenne block.

EXAMPLE 1 Preparation of Lactone of 18,9-Hydroxy-11,17a-Dimeth- 0xy-I6,8-Carb0xy-3(14) Dehydro-ZOa Yohimbane III A. Racemic lact0ne.l.5 g. of racemic lactone of ISB-hydroxy 11,17u dimethoxy-3-oxo-16fi-carboxy-2,3- seco-20u-yohimbane (I) are refluxed with 30 cc. of phosphorus oxychloride for two hours. The excess phosphorus oxychloride is expelled by distillation to dryness in vacuo, and the residue is taken up with 7.5 cc. of cold methanol. The solution is chilled to 0 C., and concentrated ammonia is added until there is alkaline reaction and no further precipitation. 30 cc. of water are added, extraction is carried out with methylene chloride, the combined extracts are dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is taken up with 30 cc. of acetone, iced and centrifuged and produces 1.175 g.- (82%) of the racemic lactone of 18;?- hydroxy-l 1, l7ot-dimethoxy- 16B caliboxy-3 14) -dehydro ZOa-yohimbane, M.P.=295-300 C. This product which has not been described previously takes the form of small yellow prismatic crystals, insoluble in water and ether, difiicultly soluble in acetone, soluble in methylene chlo ride.

Analysis.C H O N =380.43: Calculated, C percent 75 69.45; H percent 6.36; N percent 7.36; 0 percent 16.82.

Found, C percent 69.4; H percent 6.4; N percent 7.2; percent 16.9.

B. Dextrorotatory lactone-2.15 g. of the levorotatory lactone of 18B-hydroxy-11,17a-dimethoxy 3 oxo-165- carboxy-Z,3-seco-20a-yohimbane (I), [m] =-83 C. (c.=0.25%, ethanol), are refluxed with 43 cc. of phosphorus oxychloride for two hours. The excess phosphorus oxychloride is expelled by distillation to dryness in vacuo, and the residue is taken up with 43 cc. of cold methanol. This is chilled to 0 C., and concentrated ammonia is added until the reaction is alkaline and there is no more precipitation. 86 cc. of methylene chloride are added, the solution is washed with water, dried over magnesium sulfate and concentrated to small volume. After centrifuging, 1.73 g. (84%) of dextrorotatory lactone of 18,8-hydroxy-11,17a-dimethoxy 165 carboxy- 3(14)-dehydro-20u-yohimbane are isolated, Ml. above 310 C., [a] =+12 C.i (c.=0.275%, dimethylforrnamide). The product which is new takes on the form of small yellow hexagonal prisms, insoluble in water and ether, soluble in methylene chloride.

Analysis.-C H O N :380.43: Calculated, C percent 69.45; H percent 6.36; N percent 7.36; 0 percent 16.82. Found, C percent 69.0; H percent 6.3; N percent 7.2; 0 percent 16.9.

EXAMPLE 2 Preparation of Methyl A -Dehydr0reserpate (V) A. Racemic methyl A -dehydroreserpate.1.175 g. of lactone of 185-hydroxy-11,17ot-dimethoxy-16fi-carhoxy 3(14)-dehydro-20a-yohimhane (ill), prepared according to Example 1A, is introduced into 56 cc. of anhydrous methanol, and 7.2 cc. of a methanol solution of sodium methylate having 1 mg. Na/cc. is added; the solution is then heated on reflux for two hours. 0.6 cc. of acetic acid are added, the methanol is expelled in vacuo, concentrated ammonia is added until the pH is above 13, extraction is carried out with ether, the ether extract is washed with water, is dried over magnesium sulfate and is concentrated to cc. On centrifuging there is isolated 1.125 g. (88.5%) of racemic methyl N -dehydroreserpate, M.P. about 160 C. The product, which has not been described previously, takes the form of small yellow hexagonal crystals, insoluble in water, soluble in ether.

AnaZysis.C l-I O N =412.47: Calculated, C percent 66.97; H percent 6.84; N percent 6.79; O percent 19.40. Found, C percent 66.4; H percent 6.8; N percent 6.7; 0 percent 19.5.

B. Dextrorotatory methyl A394) dehydroreserpate. 1.75 g. of dextrorotatory lactone of 18,8-1ydroxy- 11,170L-dlm6llhOXY-16B carboxy 3(14) dehydro-ayohimbane (Ill), prepared according to Example 15, are introduced into 87 cc. of anhydrous methanol, and 10.4 cc. of a methanol solution of sodium methylate having 1 mg. Na/cc. are added; the solution is then heated on reflux for two hours. It is concentrated in vacuo to 3 cc., and 1.74 g. (92%) of dextrorotatory methyl A dehydroreserpate are separated, M.P.=235 C.,

(c.=0.5%, dimethylformamide). The product, which is new, is polymorphous. Recrystallized in ether, in which it is not very soluble, it melts at 170 C. It takes the form of small yellow crystals.

Analysis.C H O N =412.47I Calculated, C percent 66.97; H percent 6.84; N percent 6.79; 0 percent 19.40. Found, C percent 66.9; H percent 6.8; N percent 6.8; 0 percent 19.3.

EXAMPLE 3 Reduction of lactone of 18,8-Hydr0xy-J1,]7a-Dimeth0xy- 16f3-Carb0xy 3 (l4) -Dehydr0-20a-Y0himbane (111) 300 mg. of dextrorotatory lactone of 18fl-hydroxy- 11,17a-dimethoxy 16B carboxy 3(14) dehYdI'O-ZOOL- product thus obtained is absolutely identical with a sample of lactone of reserpic acid.

I claim: 1. 3-de'nydro-isoreserpic acid lactone of the formula a l ,u

2. The dextrorotatory lactone of 18,8-hydroxy-11,l7oc dimethoxy-16fi-carboxy-3 14) -dehydro-20a-yohimbane.

3. The method of preparing 3-dehydro-isoreserpic acid lactone of the formula 5 OCH which comprises reacting the lactone of ISB-hydroxy- 11,17a dimethoxy 3 oxo 16B carboxy-2,3-seco-20ayohimbane with phosphorus oxychloride, dissolving the reaction product in an inert organic solvent, treating with concentrated ammonia and recovering said 3-dehydro-iso reserpic acid lactone.

4. In a process of producing the lactone of 18B-hydroxy 11,170: dimethoxy 16B carboxy-3 (14)-dehydro- ZOa-yohimbane, the steps which comprise heating under reflux the lactone of 18,8-hydroxy-11,17a-dimethoxy-3- oxo 16p carboxy-2,3-seco-20a-yohimbane with phosphorus oxychloride to cause ring closure, distilling off in a vacuum excess phosphorus oxychloride, dissolving the distillation residue in methanol, and adding ammonia to the solution at a temperature of about 0 C. until the solution has attained alkaline reaction and precipitation is completed.

References Cited in the file of this patent UNITED STATES PATENTS Huebner Oct. 8, 1957 Weisenborn et a1 Mar. 28, 1961 OTHER REFERENCES UNITED STATES PATENT OFFICE CERTIFIQATE OF CRECTION Patent No. 3,051,713 August 28 1962 Georges Muller It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 6, lines 15 to 25 the formula should appear as shown below instead of as in the patent:

OCH

Signed and sealed this 22nd day of January 1963:.

(SEAL) Attest: ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents 

1. 3-DEHYDRO-ISORESERPIC ACID LACTONE OF THE FORMULA 